Primary lateral sclerosis (PLS) is a rare upper motor neuron disorder that may be related to amyotrophic lateral sclerosis (ALS). PLS differs from ALS in that patients have a long survival, and motor neurons of the spinal cord and brainstem are spared. In PLS neurodegeneration fails to spread beyond the motor cortex to any significant extent. There is considerable interest in whether PLS patients may provide clues to potential mechanisms that halt progression of neurodegeneration. Previous work from our group showed different patterns of change in white matter tracts in patients with ALS and patients with long-standing, established PLS using diffusion tensor imaging. During FY15, we continued longitudinal clinical assessments and imaging of the current cohort of patients with PLS, and recruited new patients within 5 years of symptom onset to focus on early periods of degeneration. Progress was also made on a cross-sectional analysis of diffusion tensor imaging in cohorts of patients with either PLS, ALS, and FTD to determine if clinical phenotypes could be distinguished by patterns of diffusion changes in white matter tracts. In FY15 we completed data collection as a site in a collaborative study to examine the role of oxidative stress in progression of motor neuron diseases coordinated by Columbia University. In that study (PLS-COSMOS), as part of the analysis of the baseline characteristics of 41 PLS patients, exome sequencing was carried out which identified sequence variants of different genes causing varied neurological disorders in several patients. As a new project, our group began collecting blood for genomic analysis of PLS patients with living parents (trios). This strategy, by comparing patient genomes with their unaffected parentss genomes, will help to focus on disease-causing variants that can be selected for further follow-up studies. Collection of DNA for the PLS-trio project will continue through FY16 until a sufficient number have been collected for batch sequencing.